US4434173A - Bis-esters of 4,5-di(hydroxymethyl)-2-oxo-1,3-dioxole as antibacterial agents - Google Patents

Bis-esters of 4,5-di(hydroxymethyl)-2-oxo-1,3-dioxole as antibacterial agents Download PDF

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US4434173A
US4434173A US06/441,980 US44198082A US4434173A US 4434173 A US4434173 A US 4434173A US 44198082 A US44198082 A US 44198082A US 4434173 A US4434173 A US 4434173A
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compound
formula
oxo
dioxole
group
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Willard M. Welch, Jr.
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Pfizer Corp SRL
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Pfizer Corp SRL
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Assigned to PFIZER INC. reassignment PFIZER INC. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: WELCH, WILLARD M. JR.
Priority to GR72244A priority patent/GR78684B/el
Priority to DE8383304801T priority patent/DE3364188D1/de
Priority to EP83304801A priority patent/EP0102226B1/en
Priority to IE1945/83A priority patent/IE55874B1/en
Priority to DK383283A priority patent/DK383283A/da
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C07D317/40—Vinylene carbonate; Substituted vinylene carbonates

Definitions

  • This invention relates to new chemical compounds. More particularly it relates to new chemical compounds which are of value as antibacterial agents.
  • These new antibacterial agents are bis-esters of 4,5-di(hydroxymethyl)-2-oxo-1,3-dioxole, in which one hydroxy group has been esterified with the carboxy group of 6-(2-amino-2-phenylacetamido)penicillanic acid (ampicillin) or 6-(2-amino-2-[4-hydroxyphenyl]acetamido)penicillanic acid (amoxicillin), and the other hydroxy group has been esterified with the carboxy group of penicillanic acid 1,1-dioxide (sulbactam).
  • European patent application No. 39,086, published Nov. 4, 1981 discloses esters of 4-hydroxymethyl-2-oxo-1,3-dioxole, optionally further substituted at the 5-position, in which the hydroxy group has been esterified with the carboxy group of 6-(2-amino-2-phenylacetamino)penicillanic acid.
  • U.S. Pat. No. 4,244,951 discloses bis-esters of methanediol in which one hydroxy group has been esterified with the carboxy group of certain 6-acrylaminopenicillanic acids and the other hydroxy group has been esterified using penicillanic acid 1,1-dioxide. In like manner, U.S. Pat. No.
  • 4,359,472 discloses bis-esters of di(hydroxymethyl) carbonate with certain 6-acrylaminopenicillanic acid compounds and penicillanic acid 1,1-dioxide.
  • Penicillanic acid 1,1-dioxide is known from U.S. Pat. No. 4,234,579 as an antibacterial agent and beta-lactamase inhibitor.
  • the antibacterial agents of the present invention are efficiently absorbed from the gastrointestinal tract of mammals, and after absorption they are transformed into 6-(2-amino-2-phenylacetamido)penicillanic acid (ampicillin) or 6-(2-amino-2-[4-hydroxyphenyl]acetamido)penicillanic acid (amoxicillin) and penicillanic acid 1,1-dioxide (sulbactam).
  • This invention provides new antibacterial agents of the formula ##STR1## and the pharmaceutically-acceptable acid-addition salts thereof; wherein R 1 is selected from the group consisting of phenyl and 4-hydroxyphenyl.
  • this invention embraces a method of treating a bacterial infection in a mammalian subject which comprises administering thereto an antibacterially effective amount of a compound of formula I.
  • compositions suitable for treating a bacterial infection in a mammalian subject, which comprises an antibacterially effective amount of a compound of formula I and a pharmaceutically-acceptable carrier.
  • This invention relates to derivatives of penicillanic acid, which is represented by the following structural formula ##STR2##
  • the compounds of formula I are derivatives of 4,5-dimethyl-2-oxo-1,3-dioxole, which is the compound of the formula ##STR3##
  • the compound of formula III is named 4,5-dimethyl-1,3-dioxolen-2-one in published European patent application No. 39,086.
  • the compounds of formula I can be prepared by reacting a compound of the formula ##STR5## with a compound of the formula ##STR6## wherein R 1 is phenyl or 4-hydroxyphenyl, Q is an amino protecting group, and A and B are each selected from the group consisting of M and a group of the formula ##STR7## wherein
  • M is a carboxylate salt forming cation and X is a good leaving group
  • Useful groups for Q are 1-methyl-2-alkoxycarbonylvinyl groups such as the 1-methyl-2-methoxycarbonylvinyl group; useful leaving groups for X are halogen atoms, such as chloro, bromo and iodo; and, when A or B is M, useful carboxylate salts for compound V or VI are alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and barium salts; tertiary amine salts, such as trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine and N,N-dimethylpiperazine salts; and tetraalkylammonium salts, such as tetramethylammonium and tetra-n-butylammonium
  • the reaction between a compound of the formula V and a compound of formula VI is usually carried out by contacting the reagents in a reaction-inert, organic solvent, at a temperature in the range from 0° to 80° C., and preferably from 30° to 60° C.
  • the compounds of formulae V and VI are normally contacted in equimolar proportions, but an excess of either compound can be used.
  • solvents can be used, and typical solvents are low-molecular weight ketones, such as acetone and methyl ethyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and hexamethylphosphoramide.
  • the reaction temperature varies according to a number of factors, but at about 55° C. reaction times of a few hours, e.g. 2 to 4 hours are commonly used.
  • the compound of formula VIII can be isolated by conventional methods. For example, the reaction mixture can be filtered and then the solvent removed by evaporation in vacuo. The residue is then partitioned between water and a water-immiscible, volatile, organic solvent, such as ethyl acetate, and the layers are separated. The ethyl acetate layer is dried and evaporated to afford the compound of formula VIII.
  • a water-immiscible, volatile, organic solvent such as ethyl acetate
  • the compound of formula VIII can be purified, if desired, by conventional methods such as recrystallization or chromatography; alternatively, the protecting group Q can be removed from the crude product.
  • the protecting group Q is removed from a compound of formula VIII by a conventional method for that particular protecting group, but due regard must be given to the lability of the beta-lactam rings.
  • the 1-methyl-2-alkoxycarbonylvinyl groups can be removed simply by exposing the compound of formula VIII to an aqueous or partially aqueous solvent system at an acidic pH, i.e. a pH from 0.5 to 3. This is conveniently achieved by treating the compound of formula VIII with water and 1 equivalent of a strong acid, optionally in the presence of a co-solvent, at a temperature in the range from -10° to 30° C.
  • Typical examples of strong acids which can be used are hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric acid, nitric acid and sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acids and naphthalenesulfonic acids.
  • a variety of co-solvents can be used, the major requirements of such a solvent being that it is at least partially miscible with water and it does not adversely affect either the starting material or the product.
  • Typical co-solvents are low molecular weight ketones, such as acetone and low molecular weight ethers, such as tetrahydrofuran and 1,2-dimethoxyethane.
  • the reaction is usually complete within an hour, and the product is isolated by conventional methods. In many instances, it is sufficient simply to remove the co-solvent by evaporation in vacuo and remove the alkyl acetoacetate by extraction with a water-immiscible solvent such as diethyl ether.
  • a water-immiscible solvent such as diethyl ether.
  • the compound of formula VIII is treated with one equivalent of hydrochloric acid in aqueous acetone.
  • the reaction is usually complete within a short time, e.g. within one hour. Then the acetone is removed by evaporation in vacuo, and the alkyl acetoacetate byproduct is removed by extraction with ether.
  • the compound of formula I is isolated by partitioning the residue between a volatile, water-immiscible organic solvent, such as dichloromethane, and saturated sodium chloride solution. Separation of the layers, followed by drying and evaporating the organic layer, affords the compound of formula I as its hydrochloride salt.
  • a volatile, water-immiscible organic solvent such as dichloromethane
  • saturated sodium chloride solution a volatile, water-immiscible organic solvent
  • the hydrochloride salt of the compound of formula I can be converted into the corresponding free base compound by standard methods for penicillin compounds.
  • the hydrochloride salt can be reacted with one molar equicalent of sodium bicarbonate in a two-phase system of water and dichloromethane. Separation of the layers, followed by evaporation of dichloromethane, affords the free base compound.
  • the compounds of formula I will form acid-addition salts other than the hydrochloride salt, and all of the acid-addition salts of compounds of the formula I are to be considered to be within the scope and purview of this invention.
  • Said acid addition salts are prepared by standard methods for penicillin compounds, for example by combining a solution of the compound of formula I in a suitable solvent (e.g. water, ethyl acetate, acetone, methanol, ethanol or butanol) with a solution containing a stoichiometric equivalent of the appropriate acid. If the salt precipitates, it is recovered by filtration. Alternatively, it can be recovered by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization.
  • a suitable solvent e.g. water, ethyl acetate, acetone, methanol, ethanol or butanol
  • sulfate hydrochloride, hydrobromide, nitrate, phosphate, citrate, tartrate, pamoate, perchlorate, sulfosalicylate, benzenesulfonate, 4-toluenesulfonate and 2-naphthalenesulfonate salts.
  • salts of an antibacterial compound of this invention When contemplating therapeutic use for a salt of an antibacterial compound of this invention, it is necessary to use a pharmaceutically-acceptable salt; however, salts other than these can be used for a variety of purposes. Such purposes include isolating and purifying particular compounds, and interconverting pharmaceutically-acceptable salts and their non-salt counterparts.
  • the compounds of the formula I and the salts thereof can be purified by conventional methods for penicillin compounds, e.g. recrystallization or chromatography, but due regard must be given to the lability of the beta-lactam ring systems.
  • the compounds of formula V, wherein A is of formula VII can be prepared by reaction of a compound of the formula V, wherein A is M, with a compound of the formula ##STR9## wherein R 1 , Q, M and X are as previously defined, and Y is a good leaving group, with the proviso that Y is the same as X or a better leaving group than X.
  • Useful leaving groups for Y are chloro, bromo and iodo.
  • the reaction can be carried out using the same conditions as described earlier for the reaction of a compound of formula V with a compound of formula VI.
  • the compounds of formula VI, wherein B is of formula VII can be prepared by reaction of a compound of formula VI, wherein B is M, with a compound of formula IX, wherein R 1 , Q, M, X and Y are as previously defined. This reaction can be carried out using the same conditions as described earlier for the reaction of a compound of the formula V with a compound of formula VI.
  • the compounds of formula IX are prepared from the appropriate compound of the formula ##STR10## by standard methods.
  • Y is chloro, bromo or iodo
  • the compound of formula X is halogenated using standard procedures, typical halogenating agents being N-chlorosuccinimide, N-bromosuccinimide, chlorine, bromine and t-butyl hypoiodite.
  • X is bromo
  • a particularly useful halogenating system is N-bromosuccinimide in carbon tetrachloride. See further published European patent application No. 39,477.
  • the compounds of formula I possess in vivo antibacterial activity in mammals, and this activity can be demonstrated by standard techniques for penicillin compounds.
  • the compound of formula I is administered to mice in which acute infections have been established by intraperitoneal inoculation with a standardized culture of a pathogenic bacterium. Infection severity is standardized such that the mice receive one to ten times the LD 100 (LD 100 : the minimum inoculation required to consistently kill 100 percent of control mice).
  • LD 100 the minimum inoculation required to consistently kill 100 percent of control mice.
  • the activity of the compound is assessed by counting the number of survivors which have been challenged by the bacterium and also have received the compound of formula I.
  • the compounds of formula I can be administered by both the oral (p.o.) and subcutaneous (s.c.) route.
  • the in vivo activity of the antibacterial compounds of this invention makes them suitable for the control of bacterial infections in mammals, including man, by both the oral and parenteral modes of administration.
  • the compounds are useful in the control of infections caused by susceptible bacteria in human subjects.
  • a compound of formula I breaks down to 6-(2-amino-2-phenylacetamido)penicillanic acid (ampicillin) and penicillanic acid 1,1-dioxide (sulbactam), or 6-(2-amino-2-[4-hydroxyphenyl]acetamido)penicillanic acid (amoxicillin) and penicillanic acid 1,1-dioxide (sulbactam), after administration to a mammalian subject by both the oral and parenteral route. Sulbactam then functions as a beta-lactamase inhibitor, and it increases the antibacterial effectiveness of the ampicillin or amoxicillin.
  • the compounds of the formula I will find use in the control of bacteria which are susceptible to a 1:1 mixture of ampicillin and sulbactam, or amoxicillin and sulbactam, e.g. susceptible strains of Escherichia coli and Staphylococcus aureus.
  • the in vivo test described earlier can be used.
  • the minimum inhibitory concentration (MIC) of a 1:1 mixture of ampicillin and sulbactam, or amoxicillin and sulbactam can be measured.
  • the MIC's can be measured by the procedure recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericcson and Sherris, Acta. Pathologica et Microbiologia Scandinav, Supp. 217, Section B: 64-68 [1971]), which employs brain heart infusion (BHI) agar and the inocula replicating device.
  • BHI brain heart infusion
  • Overnight growth tubes are diluted 100 fold for use as the standard inoculum (20,000-10,000 cells in approximately 0.002 ml are placed on the agar surface; 20 ml of BHI agar/dish). Twelve two-fold dilutions of the test compound are employed, with initial concentration of the test drug being 200 mcg/ml. Single colonies are disregarded when reading plates after 18 hrs. at 37° C. The susceptibility (MIC) of the test organism is accepted as the lowest concentration of compound capable of producing complete inhibition of growth as judged by the naked eye.
  • MIC susceptibility
  • an antibacterial compound of this invention When using an antibacterial compound of this invention, or a salt thereof, in a mammal, particularly man, the compound can be administered alone, or it can be mixed with other antibiotic substances and/or pharmaceutically-acceptable carriers or diluents. Said carrier or diluent is chosen on the basis of the intended mode of administration.
  • an antibacterial compound of this invention when considering the oral mode of administration, can be used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like, in accordance with standard pharmaceutical practice.
  • the proportional ratio of active ingredient to carrier will naturally depend on the chemical nature, solubility and stability of the active ingredient, as well as the dosage contemplated.
  • weight ratios in the range from 1:4 to 4:1 can conveniently be used.
  • carriers which are commonly used include lactose, sodium citrate and salts of phosphoric acid.
  • Various disintegrants such as starch, and lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are commonly used in tablets.
  • useful diluents are lactose and high molecular weight polyethylene glycols, e.g. polyethylene glycols having molecular weights of from 2000 to 4000.
  • the active ingredient is combined with emulsifying and suspending agents.
  • sweetening and/or flavoring agents can be added.
  • parenteral administration which includes intramuscular, intraperitoneal, subcutaneous, and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions are suitably adjusted and buffered.
  • the total concentration of solutes should be controlled to render the preparation isotonic.
  • the antibacterial compounds of this invention are of use in human subjects and the daily dosages to be used will not differ significantly from other, clinically-used, penicillin antibiotics.
  • the prescribing physician will ultimately determine the appropriate dose for a given human subject, and this can be expected to vary according to the age, weight, and response of the individual patient as well as the nature and the severity of the patient's symptoms.
  • the compounds of this invention will normally be used orally at dosages in the range from 20 to about 100 mg per kilogram of body weight per day, and parenterally at dosages from about 10 to about 100 mg per kilogram of body weight per day, usually in divided doses. In some instances it may be necessary to use doses outside these ranges.
  • NMR nuclear magnetic resonance
  • the title compound can be prepared by hydrolysis of 4-(6-[2-(1-methyl-2-methoxycarbonylvinylamino)-2-(4-hydroxyphenyl)acetamido]penicillanoyloxymethyl)-5-(1,1-dioxopenicillanoyloxymethyl)-2-oxo-1,3-dioxole using 0.1 N hydrochloric acid, according to the procedure of Example 1.
  • the title compound can be prepared by coupling 4-(6-[2-(1-methyl-2-methoxycarbonylvinylamino)-2-(4-hydroxyphenyl)acetamido]penicillanoyloxymethyl)-5-bromomethyl-2-oxo-1,3-dioxole with sodium penicillanate 1,1-dioxide according to the procedure of Example 4.
  • the title compound can be prepared by coupling 4-(6-[2-(1-methyl-2-propoxycarbonylvinylamino)-2-phenylacetamido]penicillanoyloxymethyl)-5-bromomethyl-2-oxo-1,3-dioxole with sodium penicillanate 1,1-dioxide according to the procedure of Example 4.
  • the title compound can be prepared by coupling sodium 6-(2-[1-methyl-2-methoxycarbonylvinylamino]-2-phenylacetamido)penicillanate with 4-(1,1-dioxopenicillanoyloxymethyl)-5-bromomethyl-2-oxo-1,3-dioxole according to the procedure of Example 4.
  • the title compound can be prepared by reaction of the tetra-n-butylammonium salt of 6-(2-[1-methyl-2-methoxycarbonylvinylamino]-2-[4-hydroxyphenyl]acetamido)penicillanic acid with 4,5-di(bromomethyl)-2-oxo-1,3-dioxole, according to the procedure of Example 8.
  • the title compound can be prepared by reaction of the tetra-n-butylammonium salt of 6-(2-[1-methyl-2-propoxycarbonylvinylamino]-2-phenylacetamido)penicillanic acid with 4,5-di(bromomethyl)-2-oxo-1,3-dioxole, according to the procedure of Example 8.
  • the title compound can be prepared by reaction of the tetra-n-butylammonium salt of penicillanic acid 1,1-dioxide with 4,5-di(bromomethyl)-2-oxo-1,3-dioxide, according to the procedure of Example 8.
  • the NMR spectrum (CDCl 3 ) showed absorptions at 2.05 (5% of starting material), 2.18 (3H, s), 4.30 (2H, s) and 4.35 (5% of dibromo compound) ppm downfield from tetramethylsilane.
  • the IR spectrum showed an absorption at 5.49 microns.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US06/441,980 1982-08-23 1982-11-15 Bis-esters of 4,5-di(hydroxymethyl)-2-oxo-1,3-dioxole as antibacterial agents Expired - Lifetime US4434173A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US06/441,980 US4434173A (en) 1982-08-23 1982-11-15 Bis-esters of 4,5-di(hydroxymethyl)-2-oxo-1,3-dioxole as antibacterial agents
GR72244A GR78684B (en:Method) 1982-08-23 1983-08-18
DE8383304801T DE3364188D1 (en) 1982-08-23 1983-08-19 Bis-esters of 4,5-di(hydroxymethyl)-2-oxo-1,3-dioxole as antibacterial agents
EP83304801A EP0102226B1 (en) 1982-08-23 1983-08-19 Bis-esters of 4,5-di(hydroxymethyl)-2-oxo-1,3-dioxole as antibacterial agents
IE1945/83A IE55874B1 (en) 1982-08-23 1983-08-19 Bis-esters of 4,5-di(hydroxymethyl)-2-oxo-1,3-dioxole as anti-bacterial agents
DK383283A DK383283A (da) 1982-08-23 1983-08-22 Fremgangsmaade til fremstilling af bis-estere af 4,5-di(hydroxymethyl)-2-oxo-1,3-dioxol

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US41076282A 1982-08-23 1982-08-23
US06/441,980 US4434173A (en) 1982-08-23 1982-11-15 Bis-esters of 4,5-di(hydroxymethyl)-2-oxo-1,3-dioxole as antibacterial agents

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EP (1) EP0102226B1 (en:Method)
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DK (1) DK383283A (en:Method)
GR (1) GR78684B (en:Method)
IE (1) IE55874B1 (en:Method)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000068225A1 (de) * 1999-05-05 2000-11-16 Bayer Aktiengesellschaft Substituierte benzimidazole, ihre herstellung und ihre verwendung als mittel gegen parasitäre protozoen
CN100384857C (zh) * 2003-11-28 2008-04-30 浙江永宁制药厂 耐β-内酰胺酶的头孢菌素酯化合物及其盐
CN103145688A (zh) * 2013-04-02 2013-06-12 黄冈鲁班药业有限公司 4，5-二氯甲基-1，3-二氧杂环戊烯-2-酮的制备方法
US20220296594A1 (en) * 2019-05-08 2022-09-22 Massachusetts Institute Of Technology Potentiators of antimicrobial and/or antiviral agents

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US6421434B1 (en) 1998-11-25 2002-07-16 Telefonaktiebolaget L M Ericsson (Publ) System for the marketing of telecommunications traffic capacity
SE525848C2 (sv) * 2002-12-17 2005-05-10 Volvo Lastvagnar Ab Rangeringsanordning för ett fordon samt en metod för att underlätta rangering av fordon
TWI877179B (zh) 2019-06-27 2025-03-21 德商百靈佳殷格翰國際股份有限公司 抗-angpt2抗體

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US4234579A (en) 1977-06-07 1980-11-18 Pfizer Inc. Penicillanic acid 1,1-dioxides as β-lactamase inhibitors
US4244951A (en) 1979-05-16 1981-01-13 Pfizer Inc. Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide
US4342693A (en) 1980-04-30 1982-08-03 Kanebo Ltd. 1,3-Dioxolen-2-one derivatives and process for production thereof
US4351840A (en) 1981-09-18 1982-09-28 Pfizer Inc. Antibacterial esters of resorcinol with ampicillin and penicillanic acid 1,1-dioxide derivatives
US4359472A (en) 1981-12-22 1982-11-16 Pfizer Inc. Bis-hydroxymethyl carbonate bridged antibacterial agents
US4389408A (en) 1980-04-30 1983-06-21 Kanebo Ltd. Novel ampicillin esters and production thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4234579A (en) 1977-06-07 1980-11-18 Pfizer Inc. Penicillanic acid 1,1-dioxides as β-lactamase inhibitors
US4244951A (en) 1979-05-16 1981-01-13 Pfizer Inc. Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide
US4342693A (en) 1980-04-30 1982-08-03 Kanebo Ltd. 1,3-Dioxolen-2-one derivatives and process for production thereof
US4389408A (en) 1980-04-30 1983-06-21 Kanebo Ltd. Novel ampicillin esters and production thereof
US4351840A (en) 1981-09-18 1982-09-28 Pfizer Inc. Antibacterial esters of resorcinol with ampicillin and penicillanic acid 1,1-dioxide derivatives
US4359472A (en) 1981-12-22 1982-11-16 Pfizer Inc. Bis-hydroxymethyl carbonate bridged antibacterial agents

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000068225A1 (de) * 1999-05-05 2000-11-16 Bayer Aktiengesellschaft Substituierte benzimidazole, ihre herstellung und ihre verwendung als mittel gegen parasitäre protozoen
US6569881B1 (en) 1999-05-05 2003-05-27 Bayer Aktiengesellschaft Substituted benzimidazole, the production thereof and the use thereof as means against parasitic protozoa
CN100384857C (zh) * 2003-11-28 2008-04-30 浙江永宁制药厂 耐β-内酰胺酶的头孢菌素酯化合物及其盐
CN103145688A (zh) * 2013-04-02 2013-06-12 黄冈鲁班药业有限公司 4，5-二氯甲基-1，3-二氧杂环戊烯-2-酮的制备方法
US20220296594A1 (en) * 2019-05-08 2022-09-22 Massachusetts Institute Of Technology Potentiators of antimicrobial and/or antiviral agents

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EP0102226B1 (en) 1986-06-18
DK383283A (da) 1984-02-24
IE55874B1 (en) 1991-02-14
EP0102226A1 (en) 1984-03-07
GR78684B (en:Method) 1984-09-27
IE831945L (en) 1984-05-15
DK383283D0 (da) 1983-08-22
DE3364188D1 (en) 1986-07-24

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